Atherosclerosis, metabolic syndrome and obesity, and their ensuing manifestations as coronary artery and stroke disease remain the major cause of death in the US and in our VA Health Care system. A major risk factor for these conditions is cholesterol and manipulation of diet is the mainstay in managing these issues. The pathway how our bodies regulate dietary cholesterol was elucidated by our recent work on a genetic disorder, sitosterolemia, which is associated with premature atherosclerotic disease. This pathway has shed light onto how dietary sterols (cholesterol and plant sterols) traffic at the intestinal and hepatocyte level regulated by the proteins ABCG5/ABCG8. Research over the past 5y involving several thousand subjects worldwide has implicated genetic variations (SNPs) in ABCG5 or ABCG8 to affect metabolic syndrome parameters, cholesterol and plasma plant sterols levels, gall stone formation, LDL-C kinetics and responsiveness to statins. At the same time, a large and burgeoning food industry has been marketing functional foods that deliver pharmacological amounts of plant sterols (or their derivatives) to 'help lower cholesterol'. These diets have been demonstrated to lower plasma cholesterol, but also increase plasma plant sterol levels. What has not been demonstrated is that the use of these foods leads to improvement in outcome. And there are no studies to suggest that these small increases in plant sterols are safe long-term. Many physicians believe that these plant sterols are 'innocuous'and thus are likely to be safe. This research aims to investigate the important role of diet, and specifically dietary plant sterols, on adipose tissue function. We have developed mouse models that affect Abcg5/Abcg8, and afford an 'at-risk'model that can amplify effects of plant sterols in the diet, which may shed light on potential issues with humans eating functional foods. We show that Abcg8 knockout mice, exposed to a plant sterol diet, have significantly reduced life expectancy, are infertile and manifest reduced adipose tissue stores. Additionally there are subtle changes in adrenal function. All of these metabolic alterations are reversible by excluding plant sterols and point to these xenosterols being biologically potent. The relationship between diet and cardiovascular disease has therapeutic implications, and a better understanding of dietary sterol trafficking should allow us to formulate better ways to modify diet. This research proposal aims to characterize the biological effects. PUBLIC HEALTH RELEVANCE: Heart disease, stroke and hypertension remain the major cause of death and disability in the VA patient population. For stroke alone, 15,000 veterans are hospitalized each year, for ischemic heart disease, between 11,000 and 13,000 VA veterans were hospitalized. The major foundation to treat these conditions remains diet and life-style changes, with the addition of pharmacotherapy. While most veterans understand and some follow the importance of such advice, a new focus is the increasing use of health-promoting foods. This work focuses on the use of foods pharmacologically-fortified with plant sterols (or their derivatives) promoted to improve cardiovascular health. These foods have not been subjected to any outcome trials nor has sufficient attention been paid to address if these foods may pose a long-term health risk. Some data from animal studies indicate improvement in atherosclerosis, but aggravation of stroke. These studies are important because they may help guide nutritional advice for a very large proportion of the patient population.